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The globular-shaped proteins, called amyloid beta-derived diffusible ligands (or ADDLs), were identified by a team of neuroscientists at Northwestern University, Evanston Northwestern Healthcare and the University of Southern California, Los Angeles.

A report on the group's findings appears in the May 26 issue of the Proceedings of the National Academy of Sciences.

ADDLs are a surprising new form of the amyloid beta protein. Amyloid beta has been known for years to accumulate as enormous fibers in Alzheimer's afflicted brains. A long-standing hypothesis has been that these fibers attack nerve cells and cause Alzheimer's dementia. These scientists now have found that ADDLs, which are minuscule clumps of amyloid beta only a tiny fraction the size of a fiber, may be more relevant to the disease process.

Their experiments in laboratory specimens found that, even at highly dilute concentrations, ADDLs interfere with long-term potentiation, one of the nerve cell processes that is essential to learning and memory. This dysfunction occurred well in advance of the cellular degeneration considered by many researchers to be the cause of Alzheimer's disease. Cell death, when it did occur, was most evident in the hippocampus, the brain's "storage bin" for short-term memory, said William L. Klein, senior author on this study. Klein is a professor of neurobiology and physiology and of neurology at Northwestern.

"Our work suggests that corruption of such signaling by ADDLs may account for the loss of synaptic memory formation at the early stages of Alzheimer's disease and for the nerve cell death and profound dementia at end stages of the disease," he said.

ADDLs apparently form when certain inflammatory proteins are present in the brain. One such protein, clusterin (or Apo J), is elevated in the brains of patients with Alzheimer's disease. Earlier research conducted by Grant A. Krafft and Caleb E. Finch, two of the investigators on this study, found that clusterin could make amyloid protein toxic but prevented formation of fibrils. Based on these results, the collaborative group subsequently found that a combination of amyloid and clusterin results in the formation of ADDLs.

Another of the researchers, Mary P. Lambert, developed tests to determine how ADDLs destroy nerve cells. These included use of a genetically modified animal which showed that ADDLs act through their receptors to activate a protein known as Fyn, a reaction that ultimately results in cell death. Neurons in the brains of people with Alzheimer's disease have been found to have elevated amounts of Fyn.

In brain slices of animals lacking the Fyn gene, ADDL-evoked cell death did not occur, showing that the mechanism through which ADDLs exert their toxicity is blocked by removal of Fyn. Furthermore, blocking ADDL binding sites also afforded neurons protection against the toxic effects of ADDLs.

Finch said the group's results are significant because: "Dogma holds that fibrils cause Alzheimer's disease. But we have found that even without fibrils, there can be devastating consequences for nerve cells," he said.

Krafft added, "While it is generally believed that Alzheimer's disease symptoms are due to nerve cell death, we were able to block memory mechanisms without nerve cell death. The implications of this work are that, if Alzheimer's disease symptoms are caught at early stages, they potentially could be reversed."

Grant A. Krafft is director of research development at Evanston Northwestern Heathcare in Evanston, Ill., and a research professor of neurology at Northwestern University Medical School. Caleb E. Finch is a professor of neurogerontology at the University of Southern California, Los Angeles. Mary P. Lambert is a senior research associate in neurobiology and physiology at Northwestern University. Other collaborators on this study included Barbara Trommer, M.D., an assistant professor of neurobiology and physiology at the Medical School and a pediatric neurologist at Evanston Northwestern Healthcare; A. K. Barlow, B. A. Chromy, R. Freed, M. Liosatos and C. Zhang, department of neurobiology and physiology, Northwestern University; C. Edwards, Evanston Hospital Research Division, Evanston, Ill.; and T. E. Morgan, I. Rozovsky and P. Wals, Andrus Gerontology Center, department of biological sciences, University of Southern California, Los Angeles.

This study was supported by grants from the National Institutes of Health (Klein, Krafft and Finch) and from the Boothroyd and Buehler Foundations and the Alzheimer's Association (Klein).

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The above story is based on materials provided by Northwestern University. Note: Materials may be edited for content and length.

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